The title compound (systematic name: methyl 2-{2-[(tert-butoxycarbonyl)amino]-2-methylpropanamido}-2-methylpropanoate), C14H26N2O5, (I), crystallizes in the monoclinic space group P21/n in two polymorphic forms, each with one molecule in the asymmetric unit. The molecular conformation is essentially the same in both polymorphs, with the α-aminoisobutyric acid (Aib) residues adopting φ and ψ values characteristic of α-helical and mixed 310- and α-helical conformations. The helical handedness of the C-terminal residue (Aib2) is opposite to that of the N-terminal residue (Aib1). In contrast to (I), the closely related peptide Boc-Aib-Aib-OBn (Boc is tert-butoxycarbonyl and Bn is benzyl) adopts an αL-PII backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen-bonded parallel β-sheet-like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen-bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one α,α-disubstituted residue.
Supporting information
CCDC references: 842135; 842136
α-Aminoisobutyric acid methyl ester hydrochloride was obtained by treating
aminoisobutyric acid with thionyl chloride in methanol solution (Jacobsen
et al., 2011). Compound (I) was synthesized by standard
solution-phase
peptide coupling of α-aminoisobutyric acid methyl ester, which was generated
in situ from α-aminoisobutyric acid methyl ester hydrochloride by
treatment with N,N-diisopropylethylamine, with commercially
available N-(tert-butoxycarbonyl)-α-aminoisobutyric acid.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) was used as coupling
reagent and 1.0 equivalent of 1-hydroxybenzotriazole (HOBt) was added to
catalyse the reaction (Jacobsen et al., 2011). A small quantity
of (I)
(about 5 mg) was dissolved in ethyl acetate (30 µl). Needle-shaped crystals
appeared as water vapour diffused into the solution at room temperature. Data
were first collected under ambient conditions because of a temporary failure
of the low-temperature device. When the cooling unit was available again, data
were recorded for a second crystal taken from the same batch. Although there
were no obvious differences in appearance, this crystal proved to be a
different polymorph. We thus had data for two concomitant forms, A
(data collected at low temperature) and B (ambient). Several other
crystals were subsequently tested to find a good specimen for collection of a
low-temperature data set for form B (the original crystal had
unfortunately been lost), but only crystals of form A were found,
suggesting that A was the dominant polymorph in the crystalline
sample. The A crystals can also be cooled and heated without being
converted to form B.
Positional parameters were refined for H atoms bonded to N. Methyl H atoms were
positioned with idealized geometry and fixed at C—H = 0.98 (form A,
105 K) or 0.96 Å (form B, 293 K), with free group rotation
permitted. Uiso(H) values were set to 1.2Ueq(N) for N—H
groups or 1.5Ueq(C) for methyl groups.
For both compounds, data collection: APEX2 (Bruker, 2007); cell refinement: SAINT-Plus (Bruker, 2007); data reduction: SAINT-Plus (Bruker, 2007). Program(s) used to solve structure: SHELXS97 (Sheldrick, 2008) for (IA); SHELXTL (Sheldrick, 2008) for (IB). Program(s) used to refine structure: SHELXL97 (Sheldrick, 2008) for (IA); SHELXTL (Sheldrick, 2008) for (IB). Molecular graphics: SHELXL97 (Sheldrick, 2008) for (IA); SHELXTL (Sheldrick, 2008) for (IB). Software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) for (IA); SHELXTL (Sheldrick, 2008) for (IB).
(IA) methyl 2-{2-[(
tert-butoxycarbonyl)amino]-2-methylpropanamido}-2-
methylpropanoate
top
Crystal data top
C14H26N2O5 | F(000) = 656 |
Mr = 302.37 | Dx = 1.178 Mg m−3 |
Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2yn | Cell parameters from 1531 reflections |
a = 6.116 (3) Å | θ = 2.3–22.9° |
b = 15.662 (7) Å | µ = 0.09 mm−1 |
c = 17.967 (8) Å | T = 105 K |
β = 97.878 (6)° | Needle, colourless |
V = 1704.7 (13) Å3 | 0.78 × 0.22 × 0.13 mm |
Z = 4 | |
Data collection top
Bruker APEXII CCD area-detector diffractometer | 4100 independent reflections |
Radiation source: fine-focus sealed tube | 2595 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.048 |
Detector resolution: 8.3 pixels mm-1 | θmax = 28.3°, θmin = 1.7° |
Sets of exposures each taken over 0.5° ω rotation scans | h = −7→7 |
Absorption correction: multi-scan (SADABS; Bruker, 2007) | k = −20→20 |
Tmin = 0.917, Tmax = 0.988 | l = −19→23 |
11873 measured reflections | |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.050 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.126 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.02 | w = 1/[σ2(Fo2) + (0.0537P)2 + 0.0954P] where P = (Fo2 + 2Fc2)/3 |
4100 reflections | (Δ/σ)max < 0.001 |
196 parameters | Δρmax = 0.28 e Å−3 |
0 restraints | Δρmin = −0.24 e Å−3 |
Crystal data top
C14H26N2O5 | V = 1704.7 (13) Å3 |
Mr = 302.37 | Z = 4 |
Monoclinic, P21/n | Mo Kα radiation |
a = 6.116 (3) Å | µ = 0.09 mm−1 |
b = 15.662 (7) Å | T = 105 K |
c = 17.967 (8) Å | 0.78 × 0.22 × 0.13 mm |
β = 97.878 (6)° | |
Data collection top
Bruker APEXII CCD area-detector diffractometer | 4100 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 2007) | 2595 reflections with I > 2σ(I) |
Tmin = 0.917, Tmax = 0.988 | Rint = 0.048 |
11873 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.050 | 0 restraints |
wR(F2) = 0.126 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.02 | Δρmax = 0.28 e Å−3 |
4100 reflections | Δρmin = −0.24 e Å−3 |
196 parameters | |
Special details top
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell e.s.d.'s are taken
into account individually in the estimation of e.s.d.'s in distances, angles
and torsion angles; correlations between e.s.d.'s in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s.
planes. |
Refinement. Refinement of F2 against ALL reflections. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | 0.09767 (19) | 0.68880 (8) | 0.36081 (7) | 0.0269 (3) | |
O2 | 0.45547 (19) | 0.71312 (8) | 0.34527 (7) | 0.0277 (3) | |
O3 | 0.72116 (18) | 0.64847 (7) | 0.19357 (6) | 0.0220 (3) | |
O4 | 0.9903 (2) | 0.47659 (8) | 0.19011 (8) | 0.0312 (3) | |
O5 | 0.6676 (2) | 0.47866 (8) | 0.11345 (7) | 0.0285 (3) | |
N1 | 0.1923 (2) | 0.68455 (9) | 0.24668 (8) | 0.0207 (3) | |
H1 | 0.058 (3) | 0.6733 (11) | 0.2340 (10) | 0.025* | |
N2 | 0.4834 (2) | 0.55241 (9) | 0.22886 (8) | 0.0224 (3) | |
H2 | 0.348 (3) | 0.5420 (12) | 0.2336 (10) | 0.027* | |
C1 | 0.1352 (3) | 0.69730 (12) | 0.44301 (9) | 0.0271 (4) | |
C2 | 0.2080 (4) | 0.78695 (13) | 0.46457 (11) | 0.0379 (5) | |
H21 | 0.3545 | 0.7973 | 0.4500 | 0.057* | |
H22 | 0.2146 | 0.7941 | 0.5190 | 0.057* | |
H23 | 0.1024 | 0.8278 | 0.4387 | 0.057* | |
C3 | −0.0916 (3) | 0.67973 (15) | 0.46398 (11) | 0.0395 (5) | |
H31 | −0.1361 | 0.6213 | 0.4494 | 0.059* | |
H32 | −0.1979 | 0.7202 | 0.4378 | 0.059* | |
H33 | −0.0880 | 0.6863 | 0.5184 | 0.059* | |
C4 | 0.2974 (3) | 0.63059 (14) | 0.47723 (12) | 0.0407 (5) | |
H41 | 0.2426 | 0.5736 | 0.4617 | 0.061* | |
H42 | 0.3139 | 0.6349 | 0.5321 | 0.061* | |
H43 | 0.4408 | 0.6400 | 0.4601 | 0.061* | |
C5 | 0.2657 (3) | 0.69746 (11) | 0.32006 (10) | 0.0219 (4) | |
C6 | 0.3401 (3) | 0.69276 (10) | 0.19011 (9) | 0.0191 (4) | |
C7 | 0.4276 (3) | 0.78329 (11) | 0.18544 (10) | 0.0236 (4) | |
H71 | 0.5107 | 0.7993 | 0.2340 | 0.035* | |
H72 | 0.3036 | 0.8227 | 0.1729 | 0.035* | |
H73 | 0.5247 | 0.7861 | 0.1464 | 0.035* | |
C8 | 0.2099 (3) | 0.66718 (11) | 0.11472 (10) | 0.0247 (4) | |
H81 | 0.1537 | 0.6089 | 0.1181 | 0.037* | |
H82 | 0.3067 | 0.6697 | 0.0756 | 0.037* | |
H83 | 0.0858 | 0.7066 | 0.1021 | 0.037* | |
C9 | 0.5346 (3) | 0.63031 (10) | 0.20610 (9) | 0.0186 (4) | |
C10 | 0.6492 (3) | 0.48485 (11) | 0.24417 (10) | 0.0233 (4) | |
C11 | 0.7926 (3) | 0.50089 (12) | 0.31875 (11) | 0.0305 (4) | |
H111 | 0.6997 | 0.5027 | 0.3590 | 0.046* | |
H112 | 0.8695 | 0.5555 | 0.3167 | 0.046* | |
H113 | 0.9011 | 0.4548 | 0.3287 | 0.046* | |
C12 | 0.5256 (3) | 0.40033 (11) | 0.24510 (12) | 0.0317 (5) | |
H121 | 0.4334 | 0.4011 | 0.2856 | 0.048* | |
H122 | 0.6320 | 0.3534 | 0.2534 | 0.048* | |
H123 | 0.4319 | 0.3922 | 0.1968 | 0.048* | |
C13 | 0.7917 (3) | 0.48165 (11) | 0.18112 (10) | 0.0238 (4) | |
C14 | 0.7893 (4) | 0.47283 (15) | 0.05058 (12) | 0.0419 (5) | |
H141 | 0.6860 | 0.4710 | 0.0038 | 0.063* | |
H142 | 0.8791 | 0.4208 | 0.0550 | 0.063* | |
H143 | 0.8856 | 0.5228 | 0.0501 | 0.063* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0178 (6) | 0.0429 (8) | 0.0205 (7) | −0.0050 (5) | 0.0047 (5) | −0.0077 (6) |
O2 | 0.0175 (6) | 0.0404 (8) | 0.0248 (7) | −0.0046 (5) | 0.0014 (5) | −0.0008 (6) |
O3 | 0.0158 (6) | 0.0235 (6) | 0.0273 (7) | −0.0026 (5) | 0.0053 (5) | 0.0011 (5) |
O4 | 0.0193 (6) | 0.0256 (7) | 0.0499 (9) | 0.0016 (5) | 0.0092 (6) | −0.0007 (6) |
O5 | 0.0248 (7) | 0.0314 (7) | 0.0304 (7) | −0.0022 (5) | 0.0077 (5) | −0.0097 (6) |
N1 | 0.0154 (7) | 0.0267 (8) | 0.0204 (8) | −0.0020 (6) | 0.0039 (6) | −0.0038 (6) |
N2 | 0.0161 (7) | 0.0187 (8) | 0.0342 (9) | −0.0003 (6) | 0.0094 (6) | 0.0005 (6) |
C1 | 0.0224 (9) | 0.0423 (11) | 0.0169 (9) | −0.0026 (8) | 0.0034 (7) | −0.0025 (8) |
C2 | 0.0406 (12) | 0.0455 (13) | 0.0275 (11) | −0.0038 (10) | 0.0042 (9) | −0.0080 (9) |
C3 | 0.0256 (10) | 0.0702 (16) | 0.0244 (10) | −0.0075 (10) | 0.0097 (8) | −0.0102 (10) |
C4 | 0.0354 (12) | 0.0521 (14) | 0.0361 (12) | 0.0065 (10) | 0.0098 (9) | 0.0117 (10) |
C5 | 0.0199 (9) | 0.0228 (9) | 0.0237 (9) | −0.0004 (7) | 0.0052 (7) | −0.0034 (7) |
C6 | 0.0169 (8) | 0.0195 (9) | 0.0216 (9) | −0.0013 (7) | 0.0049 (6) | −0.0012 (7) |
C7 | 0.0247 (9) | 0.0199 (9) | 0.0271 (10) | −0.0002 (7) | 0.0069 (7) | −0.0001 (7) |
C8 | 0.0220 (9) | 0.0286 (10) | 0.0235 (10) | −0.0029 (7) | 0.0036 (7) | −0.0023 (8) |
C9 | 0.0185 (8) | 0.0194 (9) | 0.0181 (9) | −0.0018 (7) | 0.0032 (6) | −0.0033 (7) |
C10 | 0.0197 (8) | 0.0175 (8) | 0.0336 (10) | 0.0009 (7) | 0.0065 (7) | 0.0023 (7) |
C11 | 0.0325 (11) | 0.0268 (10) | 0.0324 (11) | −0.0002 (8) | 0.0046 (8) | 0.0060 (8) |
C12 | 0.0271 (10) | 0.0199 (9) | 0.0491 (13) | −0.0023 (8) | 0.0090 (9) | 0.0057 (8) |
C13 | 0.0215 (9) | 0.0153 (8) | 0.0351 (11) | −0.0004 (7) | 0.0056 (7) | −0.0021 (7) |
C14 | 0.0388 (12) | 0.0536 (14) | 0.0362 (12) | −0.0050 (10) | 0.0157 (9) | −0.0180 (10) |
Geometric parameters (Å, º) top
O1—C5 | 1.348 (2) | C4—H42 | 0.9800 |
O1—C1 | 1.469 (2) | C4—H43 | 0.9800 |
O2—C5 | 1.212 (2) | C6—C7 | 1.522 (2) |
O3—C9 | 1.2265 (19) | C6—C8 | 1.528 (2) |
O4—C13 | 1.206 (2) | C6—C9 | 1.536 (2) |
O5—C13 | 1.343 (2) | C7—H71 | 0.9800 |
O5—C14 | 1.438 (2) | C7—H72 | 0.9800 |
N1—C5 | 1.348 (2) | C7—H73 | 0.9800 |
N1—C6 | 1.456 (2) | C8—H81 | 0.9800 |
N1—H1 | 0.840 (19) | C8—H82 | 0.9800 |
N2—C9 | 1.337 (2) | C8—H83 | 0.9800 |
N2—C10 | 1.465 (2) | C10—C11 | 1.518 (3) |
N2—H2 | 0.86 (2) | C10—C13 | 1.522 (3) |
C1—C2 | 1.508 (3) | C10—C12 | 1.526 (2) |
C1—C4 | 1.512 (3) | C11—H111 | 0.9800 |
C1—C3 | 1.512 (3) | C11—H112 | 0.9800 |
C2—H21 | 0.9800 | C11—H113 | 0.9800 |
C2—H22 | 0.9800 | C12—H121 | 0.9800 |
C2—H23 | 0.9800 | C12—H122 | 0.9800 |
C3—H31 | 0.9800 | C12—H123 | 0.9800 |
C3—H32 | 0.9800 | C14—H141 | 0.9800 |
C3—H33 | 0.9800 | C14—H142 | 0.9800 |
C4—H41 | 0.9800 | C14—H143 | 0.9800 |
| | | |
C5—O1—C1 | 120.73 (13) | C6—C7—H72 | 109.5 |
C13—O5—C14 | 115.11 (15) | H71—C7—H72 | 109.5 |
C5—N1—C6 | 120.93 (14) | C6—C7—H73 | 109.5 |
C5—N1—H1 | 118.6 (13) | H71—C7—H73 | 109.5 |
C6—N1—H1 | 120.4 (13) | H72—C7—H73 | 109.5 |
C9—N2—C10 | 122.09 (15) | C6—C8—H81 | 109.5 |
C9—N2—H2 | 118.2 (13) | C6—C8—H82 | 109.5 |
C10—N2—H2 | 119.7 (13) | H81—C8—H82 | 109.5 |
O1—C1—C2 | 110.05 (15) | C6—C8—H83 | 109.5 |
O1—C1—C4 | 110.47 (15) | H81—C8—H83 | 109.5 |
C2—C1—C4 | 112.64 (17) | H82—C8—H83 | 109.5 |
O1—C1—C3 | 102.22 (14) | O3—C9—N2 | 122.02 (15) |
C2—C1—C3 | 110.75 (17) | O3—C9—C6 | 122.27 (15) |
C4—C1—C3 | 110.24 (17) | N2—C9—C6 | 115.50 (14) |
C1—C2—H21 | 109.5 | N2—C10—C11 | 110.32 (14) |
C1—C2—H22 | 109.5 | N2—C10—C13 | 109.64 (14) |
H21—C2—H22 | 109.5 | C11—C10—C13 | 110.01 (15) |
C1—C2—H23 | 109.5 | N2—C10—C12 | 107.29 (15) |
H21—C2—H23 | 109.5 | C11—C10—C12 | 111.17 (15) |
H22—C2—H23 | 109.5 | C13—C10—C12 | 108.35 (14) |
C1—C3—H31 | 109.5 | C10—C11—H111 | 109.5 |
C1—C3—H32 | 109.5 | C10—C11—H112 | 109.5 |
H31—C3—H32 | 109.5 | H111—C11—H112 | 109.5 |
C1—C3—H33 | 109.5 | C10—C11—H113 | 109.5 |
H31—C3—H33 | 109.5 | H111—C11—H113 | 109.5 |
H32—C3—H33 | 109.5 | H112—C11—H113 | 109.5 |
C1—C4—H41 | 109.5 | C10—C12—H121 | 109.5 |
C1—C4—H42 | 109.5 | C10—C12—H122 | 109.5 |
H41—C4—H42 | 109.5 | H121—C12—H122 | 109.5 |
C1—C4—H43 | 109.5 | C10—C12—H123 | 109.5 |
H41—C4—H43 | 109.5 | H121—C12—H123 | 109.5 |
H42—C4—H43 | 109.5 | H122—C12—H123 | 109.5 |
O2—C5—O1 | 125.44 (16) | O4—C13—O5 | 123.57 (17) |
O2—C5—N1 | 124.71 (16) | O4—C13—C10 | 124.85 (17) |
O1—C5—N1 | 109.84 (14) | O5—C13—C10 | 111.40 (15) |
N1—C6—C7 | 112.16 (14) | O5—C14—H141 | 109.5 |
N1—C6—C8 | 107.33 (14) | O5—C14—H142 | 109.5 |
C7—C6—C8 | 109.87 (14) | H141—C14—H142 | 109.5 |
N1—C6—C9 | 110.62 (13) | O5—C14—H143 | 109.5 |
C7—C6—C9 | 109.55 (14) | H141—C14—H143 | 109.5 |
C8—C6—C9 | 107.16 (13) | H142—C14—H143 | 109.5 |
C6—C7—H71 | 109.5 | | |
| | | |
C1—O1—C5—N1 | 178.22 (14) | N1—C6—C9—O3 | −144.36 (15) |
O1—C5—N1—C6 | 178.13 (14) | C7—C6—C9—O3 | −20.2 (2) |
C5—N1—C6—C9 | 58.96 (19) | C8—C6—C9—O3 | 98.94 (18) |
N1—C6—C9—N2 | 40.82 (19) | C7—C6—C9—N2 | 164.97 (15) |
C6—C9—N2—C10 | 178.12 (14) | C8—C6—C9—N2 | −75.88 (18) |
C9—N2—C10—C13 | −45.6 (2) | C9—N2—C10—C11 | 75.7 (2) |
N2—C10—C13—O5 | −50.47 (18) | C9—N2—C10—C12 | −163.09 (16) |
C5—O1—C1—C2 | 64.3 (2) | C14—O5—C13—O4 | −2.8 (2) |
C5—O1—C1—C4 | −60.7 (2) | C14—O5—C13—C10 | −178.16 (15) |
C5—O1—C1—C3 | −177.95 (16) | N2—C10—C13—O4 | 134.22 (17) |
C1—O1—C5—O2 | −0.7 (3) | C11—C10—C13—O4 | 12.7 (2) |
C6—N1—C5—O2 | −3.0 (3) | C12—C10—C13—O4 | −108.98 (19) |
C5—N1—C6—C7 | −63.7 (2) | C11—C10—C13—O5 | −171.96 (14) |
C5—N1—C6—C8 | 175.55 (14) | C12—C10—C13—O5 | 66.33 (18) |
C10—N2—C9—O3 | 3.3 (3) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O3i | 0.840 (19) | 2.12 (2) | 2.963 (2) | 175.6 (18) |
N2—H2···O4i | 0.86 (2) | 2.44 (2) | 3.227 (2) | 151.6 (17) |
C3—H32···O2i | 0.98 | 2.51 | 3.298 (2) | 137 |
C11—H112···O1ii | 0.98 | 2.57 | 3.511 (2) | 160 |
Symmetry codes: (i) x−1, y, z; (ii) x+1, y, z. |
(IB) Methyl 2-(2-{[(
tert-butoxy)carbonyl]amino}-2-methylpropanamido)-
2-methylpropanoate
top
Crystal data top
C14H26N2O5 | F(000) = 656 |
Mr = 302.37 | Dx = 1.144 Mg m−3 |
Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2yn | Cell parameters from 2025 reflections |
a = 6.0679 (15) Å | θ = 2.4–22.2° |
b = 33.743 (9) Å | µ = 0.09 mm−1 |
c = 8.583 (2) Å | T = 293 K |
β = 92.266 (3)° | Needle, colourless |
V = 1756.0 (8) Å3 | 0.80 × 0.11 × 0.10 mm |
Z = 4 | |
Data collection top
Bruker APEXII CCD area-detector diffractometer | 3105 independent reflections |
Radiation source: fine-focus sealed tube | 1584 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.052 |
Detector resolution: 8.3 pixels mm-1 | θmax = 25.1°, θmin = 2.4° |
Sets of exposures each taken over 0.5° ω rotation scans | h = −7→6 |
Absorption correction: multi-scan (SADABS; Bruker, 2007) | k = −40→40 |
Tmin = 0.814, Tmax = 0.991 | l = −8→10 |
10165 measured reflections | |
Refinement top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.042 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.125 | w = 1/[σ2(Fo2) + (0.0488P)2 + 0.216P] where P = (Fo2 + 2Fc2)/3 |
S = 1.00 | (Δ/σ)max < 0.001 |
3105 reflections | Δρmax = 0.15 e Å−3 |
197 parameters | Δρmin = −0.18 e Å−3 |
0 restraints | Extinction correction: SHELXTL (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.0055 (11) |
Crystal data top
C14H26N2O5 | V = 1756.0 (8) Å3 |
Mr = 302.37 | Z = 4 |
Monoclinic, P21/n | Mo Kα radiation |
a = 6.0679 (15) Å | µ = 0.09 mm−1 |
b = 33.743 (9) Å | T = 293 K |
c = 8.583 (2) Å | 0.80 × 0.11 × 0.10 mm |
β = 92.266 (3)° | |
Data collection top
Bruker APEXII CCD area-detector diffractometer | 3105 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 2007) | 1584 reflections with I > 2σ(I) |
Tmin = 0.814, Tmax = 0.991 | Rint = 0.052 |
10165 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.042 | 0 restraints |
wR(F2) = 0.125 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.00 | Δρmax = 0.15 e Å−3 |
3105 reflections | Δρmin = −0.18 e Å−3 |
197 parameters | |
Special details top
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell e.s.d.'s are taken
into account individually in the estimation of e.s.d.'s in distances, angles
and torsion angles; correlations between e.s.d.'s in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s.
planes. |
Refinement. Refinement of F2 against ALL reflections. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | 0.7670 (2) | 0.16039 (5) | 0.41606 (19) | 0.0514 (5) | |
O2 | 0.3981 (3) | 0.14871 (5) | 0.4262 (2) | 0.0602 (5) | |
O3 | 0.0809 (3) | 0.07826 (5) | 0.23468 (19) | 0.0539 (5) | |
O4 | −0.2053 (3) | 0.10381 (7) | −0.0755 (2) | 0.0810 (7) | |
O5 | 0.0752 (3) | 0.06320 (6) | −0.1201 (2) | 0.0741 (6) | |
N1 | 0.6337 (3) | 0.10221 (6) | 0.3412 (2) | 0.0478 (6) | |
H1 | 0.768 (4) | 0.0967 (7) | 0.322 (3) | 0.057* | |
N2 | 0.3297 (3) | 0.10786 (7) | 0.0864 (2) | 0.0490 (6) | |
H2 | 0.467 (4) | 0.1122 (7) | 0.077 (3) | 0.059* | |
C1 | 0.7528 (4) | 0.20241 (7) | 0.4585 (3) | 0.0470 (6) | |
C2 | 0.6581 (5) | 0.20702 (10) | 0.6176 (3) | 0.0777 (9) | |
H21 | 0.5063 | 0.1989 | 0.6132 | 0.117* | |
H22 | 0.6681 | 0.2343 | 0.6494 | 0.117* | |
H23 | 0.7397 | 0.1908 | 0.6915 | 0.117* | |
C3 | 0.9917 (4) | 0.21537 (9) | 0.4615 (3) | 0.0640 (8) | |
H31 | 1.0733 | 0.2011 | 0.5414 | 0.096* | |
H32 | 1.0006 | 0.2433 | 0.4828 | 0.096* | |
H33 | 1.0528 | 0.2100 | 0.3622 | 0.096* | |
C4 | 0.6211 (5) | 0.22449 (9) | 0.3336 (4) | 0.0770 (9) | |
H41 | 0.4700 | 0.2160 | 0.3335 | 0.116* | |
H42 | 0.6803 | 0.2190 | 0.2338 | 0.116* | |
H43 | 0.6291 | 0.2524 | 0.3541 | 0.116* | |
C5 | 0.5831 (4) | 0.13823 (8) | 0.3984 (3) | 0.0459 (6) | |
C6 | 0.4653 (4) | 0.07164 (7) | 0.3184 (3) | 0.0454 (6) | |
C7 | 0.3751 (4) | 0.05820 (9) | 0.4737 (3) | 0.0661 (8) | |
H71 | 0.4943 | 0.0489 | 0.5409 | 0.099* | |
H72 | 0.2705 | 0.0372 | 0.4555 | 0.099* | |
H73 | 0.3038 | 0.0801 | 0.5223 | 0.099* | |
C8 | 0.5736 (4) | 0.03674 (7) | 0.2366 (3) | 0.0654 (8) | |
H81 | 0.6942 | 0.0269 | 0.3012 | 0.098* | |
H82 | 0.6275 | 0.0454 | 0.1387 | 0.098* | |
H83 | 0.4669 | 0.0161 | 0.2187 | 0.098* | |
C9 | 0.2742 (4) | 0.08686 (7) | 0.2122 (3) | 0.0426 (6) | |
C10 | 0.1666 (4) | 0.12651 (8) | −0.0190 (3) | 0.0506 (7) | |
C11 | 0.0614 (5) | 0.16183 (8) | 0.0611 (3) | 0.0700 (8) | |
H111 | 0.1741 | 0.1803 | 0.0937 | 0.105* | |
H112 | −0.0146 | 0.1528 | 0.1504 | 0.105* | |
H113 | −0.0415 | 0.1745 | −0.0106 | 0.105* | |
C12 | 0.2843 (5) | 0.13999 (10) | −0.1641 (3) | 0.0772 (9) | |
H121 | 0.3986 | 0.1585 | −0.1345 | 0.116* | |
H122 | 0.1801 | 0.1525 | −0.2354 | 0.116* | |
H123 | 0.3480 | 0.1174 | −0.2136 | 0.116* | |
C13 | −0.0112 (4) | 0.09715 (9) | −0.0703 (3) | 0.0570 (7) | |
C14 | −0.0805 (6) | 0.03433 (11) | −0.1855 (5) | 0.1107 (13) | |
H141 | −0.0021 | 0.0112 | −0.2173 | 0.166* | |
H142 | −0.1589 | 0.0456 | −0.2741 | 0.166* | |
H143 | −0.1833 | 0.0271 | −0.1081 | 0.166* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0360 (10) | 0.0478 (11) | 0.0703 (11) | −0.0033 (8) | 0.0018 (8) | −0.0078 (9) |
O2 | 0.0362 (10) | 0.0638 (13) | 0.0809 (13) | 0.0005 (9) | 0.0082 (9) | −0.0130 (10) |
O3 | 0.0338 (10) | 0.0657 (12) | 0.0626 (11) | −0.0053 (8) | 0.0070 (8) | 0.0040 (9) |
O4 | 0.0415 (12) | 0.1102 (18) | 0.0906 (15) | 0.0075 (11) | −0.0046 (10) | −0.0053 (12) |
O5 | 0.0529 (12) | 0.0867 (15) | 0.0824 (14) | −0.0008 (11) | −0.0002 (10) | −0.0313 (12) |
N1 | 0.0320 (11) | 0.0477 (14) | 0.0637 (14) | −0.0018 (11) | 0.0034 (10) | −0.0066 (11) |
N2 | 0.0349 (11) | 0.0659 (15) | 0.0463 (12) | −0.0058 (11) | 0.0034 (10) | 0.0058 (11) |
C1 | 0.0453 (15) | 0.0449 (17) | 0.0510 (15) | −0.0020 (12) | 0.0031 (12) | −0.0062 (12) |
C2 | 0.074 (2) | 0.094 (2) | 0.066 (2) | −0.0164 (18) | 0.0191 (16) | −0.0230 (17) |
C3 | 0.0530 (17) | 0.065 (2) | 0.0742 (19) | −0.0114 (14) | 0.0033 (14) | −0.0092 (15) |
C4 | 0.074 (2) | 0.069 (2) | 0.087 (2) | 0.0006 (16) | −0.0111 (18) | 0.0103 (17) |
C5 | 0.0360 (15) | 0.0525 (18) | 0.0488 (15) | −0.0012 (13) | −0.0024 (12) | 0.0001 (13) |
C6 | 0.0359 (13) | 0.0469 (16) | 0.0535 (15) | −0.0017 (12) | 0.0023 (12) | 0.0003 (12) |
C7 | 0.0590 (17) | 0.078 (2) | 0.0605 (18) | −0.0108 (16) | −0.0018 (15) | 0.0178 (15) |
C8 | 0.0522 (16) | 0.0481 (17) | 0.096 (2) | −0.0013 (14) | 0.0031 (15) | −0.0073 (15) |
C9 | 0.0363 (14) | 0.0426 (15) | 0.0490 (15) | −0.0031 (11) | 0.0044 (12) | −0.0047 (12) |
C10 | 0.0424 (15) | 0.0651 (19) | 0.0445 (15) | 0.0024 (13) | 0.0054 (12) | 0.0052 (13) |
C11 | 0.080 (2) | 0.062 (2) | 0.0689 (19) | 0.0120 (16) | 0.0073 (17) | 0.0052 (15) |
C12 | 0.0661 (19) | 0.115 (3) | 0.0517 (17) | −0.0011 (18) | 0.0108 (15) | 0.0211 (17) |
C13 | 0.0396 (16) | 0.081 (2) | 0.0502 (16) | 0.0048 (15) | −0.0010 (12) | −0.0027 (14) |
C14 | 0.087 (2) | 0.119 (3) | 0.125 (3) | −0.022 (2) | −0.010 (2) | −0.061 (3) |
Geometric parameters (Å, º) top
O1—C5 | 1.347 (3) | C4—H42 | 0.9600 |
O1—C1 | 1.467 (3) | C4—H43 | 0.9600 |
O2—C5 | 1.210 (3) | C6—C7 | 1.530 (3) |
O3—C9 | 1.231 (3) | C6—C8 | 1.532 (3) |
O4—C13 | 1.198 (3) | C6—C9 | 1.535 (3) |
O5—C13 | 1.337 (3) | C7—H71 | 0.9600 |
O5—C14 | 1.454 (3) | C7—H72 | 0.9600 |
N1—C5 | 1.351 (3) | C7—H73 | 0.9600 |
N1—C6 | 1.460 (3) | C8—H81 | 0.9600 |
N1—H1 | 0.86 (2) | C8—H82 | 0.9600 |
N2—C9 | 1.346 (3) | C8—H83 | 0.9600 |
N2—C10 | 1.457 (3) | C10—C13 | 1.518 (4) |
N2—H2 | 0.85 (2) | C10—C11 | 1.528 (4) |
C1—C4 | 1.509 (4) | C10—C12 | 1.529 (3) |
C1—C2 | 1.511 (3) | C11—H111 | 0.9600 |
C1—C3 | 1.513 (3) | C11—H112 | 0.9600 |
C2—H21 | 0.9600 | C11—H113 | 0.9600 |
C2—H22 | 0.9600 | C12—H121 | 0.9600 |
C2—H23 | 0.9600 | C12—H122 | 0.9600 |
C3—H31 | 0.9600 | C12—H123 | 0.9600 |
C3—H32 | 0.9600 | C14—H141 | 0.9600 |
C3—H33 | 0.9600 | C14—H142 | 0.9600 |
C4—H41 | 0.9600 | C14—H143 | 0.9600 |
| | | |
C5—O1—C1 | 120.53 (18) | C6—C7—H72 | 109.5 |
C13—O5—C14 | 116.1 (2) | H71—C7—H72 | 109.5 |
C5—N1—C6 | 121.1 (2) | C6—C7—H73 | 109.5 |
C5—N1—H1 | 119.7 (16) | H71—C7—H73 | 109.5 |
C6—N1—H1 | 119.1 (16) | H72—C7—H73 | 109.5 |
C9—N2—C10 | 122.7 (2) | C6—C8—H81 | 109.5 |
C9—N2—H2 | 116.0 (17) | C6—C8—H82 | 109.5 |
C10—N2—H2 | 120.8 (17) | H81—C8—H82 | 109.5 |
O1—C1—C4 | 109.6 (2) | C6—C8—H83 | 109.5 |
O1—C1—C2 | 110.6 (2) | H81—C8—H83 | 109.5 |
C4—C1—C2 | 112.4 (2) | H82—C8—H83 | 109.5 |
O1—C1—C3 | 102.59 (19) | O3—C9—N2 | 121.3 (2) |
C4—C1—C3 | 110.5 (2) | O3—C9—C6 | 122.0 (2) |
C2—C1—C3 | 110.7 (2) | N2—C9—C6 | 116.5 (2) |
C1—C2—H21 | 109.5 | N2—C10—C13 | 110.9 (2) |
C1—C2—H22 | 109.5 | N2—C10—C11 | 110.1 (2) |
H21—C2—H22 | 109.5 | C13—C10—C11 | 109.6 (2) |
C1—C2—H23 | 109.5 | N2—C10—C12 | 107.9 (2) |
H21—C2—H23 | 109.5 | C13—C10—C12 | 107.9 (2) |
H22—C2—H23 | 109.5 | C11—C10—C12 | 110.6 (2) |
C1—C3—H31 | 109.5 | C10—C11—H111 | 109.5 |
C1—C3—H32 | 109.5 | C10—C11—H112 | 109.5 |
H31—C3—H32 | 109.5 | H111—C11—H112 | 109.5 |
C1—C3—H33 | 109.5 | C10—C11—H113 | 109.5 |
H31—C3—H33 | 109.5 | H111—C11—H113 | 109.5 |
H32—C3—H33 | 109.5 | H112—C11—H113 | 109.5 |
C1—C4—H41 | 109.5 | C10—C12—H121 | 109.5 |
C1—C4—H42 | 109.5 | C10—C12—H122 | 109.5 |
H41—C4—H42 | 109.5 | H121—C12—H122 | 109.5 |
C1—C4—H43 | 109.5 | C10—C12—H123 | 109.5 |
H41—C4—H43 | 109.5 | H121—C12—H123 | 109.5 |
H42—C4—H43 | 109.5 | H122—C12—H123 | 109.5 |
O2—C5—O1 | 125.9 (2) | O4—C13—O5 | 123.1 (3) |
O2—C5—N1 | 124.1 (2) | O4—C13—C10 | 125.1 (3) |
O1—C5—N1 | 109.9 (2) | O5—C13—C10 | 111.6 (2) |
N1—C6—C7 | 111.5 (2) | O5—C14—H141 | 109.5 |
N1—C6—C8 | 107.08 (19) | O5—C14—H142 | 109.5 |
C7—C6—C8 | 110.3 (2) | H141—C14—H142 | 109.5 |
N1—C6—C9 | 110.57 (19) | O5—C14—H143 | 109.5 |
C7—C6—C9 | 109.19 (19) | H141—C14—H143 | 109.5 |
C8—C6—C9 | 108.2 (2) | H142—C14—H143 | 109.5 |
C6—C7—H71 | 109.5 | | |
| | | |
C1—O1—C5—N1 | 172.52 (19) | N1—C6—C9—O3 | −142.0 (2) |
O1—C5—N1—C6 | 176.88 (19) | C7—C6—C9—O3 | −19.1 (3) |
C5—N1—C6—C9 | 56.4 (3) | C8—C6—C9—O3 | 101.0 (3) |
N1—C6—C9—N2 | 42.5 (3) | C7—C6—C9—N2 | 165.5 (2) |
C6—C9—N2—C10 | −175.6 (2) | C8—C6—C9—N2 | −74.4 (3) |
C9—N2—C10—C13 | −50.5 (3) | C9—N2—C10—C11 | 70.9 (3) |
N2—C10—C13—O5 | −49.1 (3) | C9—N2—C10—C12 | −168.4 (2) |
C5—O1—C1—C4 | −61.3 (3) | C14—O5—C13—O4 | 1.2 (4) |
C5—O1—C1—C2 | 63.2 (3) | C14—O5—C13—C10 | −174.6 (2) |
C5—O1—C1—C3 | −178.7 (2) | N2—C10—C13—O4 | 135.2 (3) |
C1—O1—C5—O2 | −6.2 (4) | C11—C10—C13—O4 | 13.5 (4) |
C6—N1—C5—O2 | −4.4 (4) | C12—C10—C13—O4 | −106.9 (3) |
C5—N1—C6—C7 | −65.2 (3) | C11—C10—C13—O5 | −170.8 (2) |
C5—N1—C6—C8 | 174.1 (2) | C12—C10—C13—O5 | 68.8 (3) |
C10—N2—C9—O3 | 8.9 (4) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O3i | 0.86 (2) | 2.16 (2) | 3.008 (3) | 170 (2) |
N2—H2···O4i | 0.85 (2) | 2.44 (2) | 3.197 (3) | 148 (2) |
Symmetry code: (i) x+1, y, z. |
Experimental details
| (IA) | (IB) |
Crystal data |
Chemical formula | C14H26N2O5 | C14H26N2O5 |
Mr | 302.37 | 302.37 |
Crystal system, space group | Monoclinic, P21/n | Monoclinic, P21/n |
Temperature (K) | 105 | 293 |
a, b, c (Å) | 6.116 (3), 15.662 (7), 17.967 (8) | 6.0679 (15), 33.743 (9), 8.583 (2) |
β (°) | 97.878 (6) | 92.266 (3) |
V (Å3) | 1704.7 (13) | 1756.0 (8) |
Z | 4 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.09 | 0.09 |
Crystal size (mm) | 0.78 × 0.22 × 0.13 | 0.80 × 0.11 × 0.10 |
|
Data collection |
Diffractometer | Bruker APEXII CCD area-detector diffractometer | Bruker APEXII CCD area-detector diffractometer |
Absorption correction | Multi-scan (SADABS; Bruker, 2007) | Multi-scan (SADABS; Bruker, 2007) |
Tmin, Tmax | 0.917, 0.988 | 0.814, 0.991 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 11873, 4100, 2595 | 10165, 3105, 1584 |
Rint | 0.048 | 0.052 |
(sin θ/λ)max (Å−1) | 0.667 | 0.596 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.050, 0.126, 1.02 | 0.042, 0.125, 1.00 |
No. of reflections | 4100 | 3105 |
No. of parameters | 196 | 197 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.28, −0.24 | 0.15, −0.18 |
Hydrogen-bond geometry (Å, º) for (IA) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O3i | 0.840 (19) | 2.12 (2) | 2.963 (2) | 175.6 (18) |
N2—H2···O4i | 0.86 (2) | 2.44 (2) | 3.227 (2) | 151.6 (17) |
C3—H32···O2i | 0.98 | 2.51 | 3.298 (2) | 137.2 |
C11—H112···O1ii | 0.98 | 2.57 | 3.511 (2) | 159.9 |
Symmetry codes: (i) x−1, y, z; (ii) x+1, y, z. |
Main torsion angles (°) in the crystal structures of protected dipeptides
in the CSD (Allen, 2002). topRefcodea | Sequenceb | ϕ1c | ψ1 | ϕ2 | ψT | Inv.d |
(IA) | Boc-B-B-OMe | 58.96 (19) | 40.82 (19) | -45.6 (2) | -50.47 (18) | - |
(IB) | Boc-B-B-OMe | 56.4 (3) | 42.5 (3) | -50.5 (3) | -49.1 (3) | - |
BAJROT10 | Boc-B-B-OBn | 59.6 | 52.0 | -51.5 | 138.4 | i |
PARDUH | Boc-B-B*-OMe | 61.5 | 32.8 | 177.0 | -179.4 | - |
| | 62.6 | 33.3 | 177.3 | 179.2 | - |
PUXHOF | Boc-B*-B*-OMe | 55.0 | 42.7 | -56.0 | -34.7 | i |
VEYQAR | Cbz-B*-B*-OMe | 65.5 | 26.6 | -35.5 | -50.8 | i |
AJOLEQ | Boc-B-I-OMe | 63.9 | 45.8 | -68.0 | -29.8 | - |
| | 57.2 | 44.3 | 122.1 | -148.1 | i |
CAPZIC | Boc-B*-V-OBn | 58.9 | 33.3 | -57.2 | -44.2 | - |
GANPEQ | Cbz-B-A-OtB | 57.8 | 41.8 | -78.9 | 170.54 | - |
| | 58.8 | 46.3 | 133.3 | -174.9 | i |
OBAZIA | Boc-B*-A-OMe | 56.1 | 45.8 | -95.1 | -177.9 | i |
| | 58.4 | 42.8 | 145.8 | -24.4 | - |
OFUXOC | Boc-B*-L-OMe | 60.8 | 47.1 | -72.3 | -36.2 | - |
| | 64.3 | 48.7 | 122.7 | -9.6 | i |
PASGUL | Boc-B-F-OMe | 62.1 | 44.1 | -75.9 | 1.6 | - |
| | 53.7 | 50.7 | 122.0 | -164.0 | i |
XOWVAG | Boc-B-L-OMe | 58.1 | 46.7 | -80.7 | -0.5 | - |
| | 58.4 | 44.5 | 112.9 | -165.7 | i |
LAGFII | Boc-V-B*-OMe | 73.2 | -127.3 | 55.2 | 32.2 | i |
TIRJOT | Cbz-A-B-OtB | 76.6 | -156.2 | -51.0 | -44.7 | i |
ZAQVUI | Cbz-L-B*-OMe | 90.6 | 32.2 | -43.7 | -53.1 | i |
Notes: (a) Except (IA) and (IB) (this work): refcode in the CSD.
(b) Abbreviations: Boc = tert-butoxycarbonyl; Cbz = carboxybenzyl;
B = Aib; B* = other α,α-disubstituted amino acid; I = isoleucine;
V = valine; A = alanine; F = phenylalanine; Me = methyl; Bn = benzyl;
tB = tert-butyl.
(c) For (I), with reference to Fig. 1, the listed torsion angles are:
ϕ1 = C5—N1—C6—C9, ψ1 = N1—C6—C9—N2,
ϕ2 = C9—N2—C10—C13 and ψT = N2—C10—C13—O5.
(d) To facilitate comparison between structures, molecules indicated by `i'
have been inverted to obtain the same sign for the first torsion angle ϕ1. |
Hydrogen-bond geometry (Å, º) for (IB) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O3i | 0.86 (2) | 2.16 (2) | 3.008 (3) | 170 (2) |
N2—H2···O4i | 0.85 (2) | 2.44 (2) | 3.197 (3) | 148 (2) |
Symmetry code: (i) x+1, y, z. |
α-Aminoisobutyric acid (Aib) is an achiral non-proteinogenic amino acid found in peptaibiotics, a group of fungal peptides with antibiotic activity (Degenkolb & Brückner, 2008; Toniolo & Brückner, 2009). Peptaibiotics, exemplified by alamethicin (Pandey et al., 1977), are believed to exert their biological effect by folding into amphipathic helices that oligomerize, forming voltage-gated transmembrane ion channels (Mueller & Rudin, 1968; Nagaraj & Balaram, 1981; Fox & Richards, 1982). Key to the biological activity of peptaibiotics is the (conformational) preference of Aib for helical conformations. As was first recognized by Ramachandran & Chandrasekaran (1972) and, independently, by Marshall & Bosshard (1972), the Aib residue is almost invariably restricted to ϕ and ψ values corresponding to the right- (ϕ = -60±20°, ψ = -30±20°) or left-handed (ϕ = 60±20°, ψ = 30±20°) 310- or α-helical regions of the Ramachandran plot (Venkatraman et al., 2001). It has been known for a long time that Aib can increase the conformational stability of peptide helices (Burgess & Leach, 1973; Karle & Balaram, 1990), with both α- and 310-helical hydrogen-bonding patterns (Marshall et al., 1990). The introduction of Aib residues into polypeptide chains limits the range of conformations accessible to the peptide because of the extra methyl group at the Cα atom, forcing the peptide chain into a left- or right-handed helical conformation or nucleating a β-turn (Aravinda et al., 2003). Numerous X-ray diffraction studies of short Aib-based model peptides have demonstrated their preference for 310-helical structures (Karle & Balaram, 1990; Toniolo & Benedetti, 1991; Toniolo et al., 2001). A review of crystal structures of synthetic tri-, tetra- and pentapeptides containing at least one Aib residue showed that almost all form incipient 310-helices (Toniolo et al., 1983). However, while shorter Aib peptides preferentially adopt type III/III' β-turn and 310-helical conformations, longer Aib peptides are able to form α-helical structures (Butters et al., 1981; Schmitt et al., 1982; Pavone et al., 1990).
Although 310- and α-helical conformations are statistically by far the most prevalent conformations observed for Aib in crystal structures of Aib-containing peptides, a number of Aib residues have also been found to adopt polyproline II conformations, in particular in structures of protected di- and tripeptides (Aravinda et al., 2008). Other non-helical conformations are, however, very rare. Notably, because of the severe steric clash between the carbonyl group of the preceding residue and one of the methyl groups, β-strand conformations are energetically very unfavourable (Aravinda et al., 2008), making Aib one of the best β-sheet-breaking amino acids (Moretto et al., 1989; Toniolo et al., 2001).
Aib residues at the C-terminus of a helix have a tendency to adopt a different conformation from the rest of the molecule. In a recent investigation of 143 crystal structures of Aib-containing helical peptides with more than three residues, 66.2% of the C-terminal Aib residues were found to adopt helical conformations corresponding to a different helical handedness than the body of the peptide, and 20.3% to adopt polyproline II conformations (Aravinda et al., 2008).
The title compound, (I), was synthesized as part of an ongoing effort to develop a generic methodology for the conformational stabilization of synthetic analogues of 310-helical protein segments (Jacobsen et al., 2009, 2011).
Many biologically important protein–protein interactions are mediated by helical protein segments and could therefore, in principle, be modulated by synthetic peptides with similar primary and secondary structures. Because the entropy reduction associated with ligand–receptor binding is likely to be smaller for a prestructured or conformationally restricted peptide than for a related random coil peptide, the ability of Aib to induce or stabilize helical conformations makes Aib-containing peptides mimicking protein segments potentially valuable in drug discovery. Improved proteolytic stability is another beneficial effect of a higher degree of helicity in solution (Banerjee et al., 2002), which derives from the fact that proteases recognize their substrates in a β-strand conformation (Tyndall et al., 2005).
Diffraction data were collected for two needle-shaped crystals, which proved to represent two different polymorphs of (I), hereafter denoted A and B, which both belong to the monoclinic space group P21/n (see Experimental). The molecular structure of (I) is depicted in Fig. 1. The conformation is virtually the same in both polymorphic forms, as reflected by the torsion angles listed in Table 1 and the r.m.s. value of 0.157 Å for the best fit between heavy atoms. The ϕ and ψ values are characteristic of mixed 310- and α-helical conformations. Notably, the helical handedness of the C-terminal residue Aib2 is opposite to that of the N-terminal residue Aib1 in both polymorphs, which helps to avoid unfavourable intramolecular contacts (Van Roey et al., 1983) [as (I) is achiral and crystallizes in a centrosymmetric space group, it is not meaningful to designate the conformations as left- or right-handed]. Interestingly, Aib2 in the closely related protected dipeptide Boc–Aib–Aib–OBn [Cambridge Structural Database (CSD, Version 5.32 of November 2010; Allen, 2002) refcode BAJROT10; Van Roey et al., 1983; Table 1] adopts a polyproline II conformation (or its mirror image conformation) instead of a 310-/α-helical conformation.
Pairs of hydrogen bonds (Tables 2 and 3) link the peptide molecules of (I) into chains, as shown in Fig. 2(a). In form A, the strong hydrogen bonds are supported by two C—H···O═C contacts with H···O < 2.60 Å; these are essentially missing in form B as the pertinent H···O distances are > 2.85 Å. A similar tape motif has previously only been found for Boc–α-methyl-L-Phe–L-Val–OBn (CSD refcode CAPZIC; Van Roey et al., 1981). Other protected Aib*–Xaa dipeptides in the CSD, where Aib* is either Aib or another α,α-disubstituted amino acid and Xaa is a chiral amino acid, form a second type of tape motif that in a sense constitutes a `frame shift' compared with (I), as the pair of carbonyl acceptors are shifted one residue towards the N-terminal end of the peptide, corresponding to atoms O2 and O3 in Fig. 1 rather than atoms O3 and O4 used for (I) (Tables 2 and 3). Furthermore, the Aib* residue in every second molecule in the tape adopts a conformation corresponding to the opposite helical handedness (Fig. 2b). All such structures have two molecules in the asymmetric unit, one with the same conformation as (I) (or its mirror image) and one with a different orientation of the second residue (Table 1). The same pattern is also observed for the benzyl ester analogue of (I) (BAJROT10; Van Roey et al., 1983) and for one out of three Xaa–Aib* peptides. Molecules in Table 1 with two α,α-disubstituted amino acid residues, where at least one is different from Aib, are evidently too crowded to form tape motifs and instead form various simple hydrogen-bonded chains.
Recent studies have revealed the importance of n→π* C═ Oi→ Ci+1═O hyperconjugative interactions between consecutive amide groups in stabilizing 310-helical, α-helical and polyproline II conformations (Bretscher et al., 2001; Hodges & Raines, 2006; Jakobsche et al., 2010), in particular when the distance d from atom Oi to atom Ci+1 is less than 3.2 Å (Bartlett et al., 2010). In a 310-helix, one such interaction can be worth as much as 1.3 kcal mol-1 (5.4 kJ mol-1; 1 kcal mol-1 = 4.184 kJ mol-1) (Bartlett et al., 2010). If an ester is the electron-density acceptor, it has been found that an n→π* C═Oi→ Ci+1═O interaction can provide 0.7 kcal mol-1 of stabilization energy (Hinderaker & Raines, 2003). The observed Oi to Ci+1distances are 2.916 (2) and 2.663 (2) Å for Aib1 and Aib2, respectively, in polymorph A, while the corresponding values for polymorph B are 2.861 (3) and 2.730 (3) Å. The crystal structures of (I) thus provide good examples of n→π* C═ Oi→ Ci+1═O stabilizing interactions in a short peptide. A helical or polyproline II conformation allows the lone pair on the carbonyl O atom to interact with the antibonding Ci+1═O orbital along an angle of attack very close to the Bürgi–Dunitz angle (107°), the preferred angle of attack of a nucleophile at a carbonyl group (Bürgi et al., 1973). Significantly, the Oi—C═ Oi+1 angles for both polymorphic forms of (I) are very close to the Bürgi–Dunitz angle, with values of 108.80 (11) and 103.01 (11)° for Aib 1 and Aib 2, respectively, in polymorph A, and 107.42 (16) and 104.08 (18)°, respectively, in polymorph B.
The overall crystal packing arrangements of the two polymorphs, illustrated in Fig. 3, are quite different, despite the occurrence of hydrogen-bonded tapes in both forms, as shown in Fig. 2. In the B form, the tert-butyl groups are more closely aggregated in the ac plane, as a result of the short c axis.